OBJECTIVE: To describe the prevalence of physical inactivity and associated factors among high school students from state's public schools in the city of São Paulo, state of São Paulo, Brazil. METHODS: Sixteen state's public schools were randomly selected according to the geographic areas of the city (North, South, East, and West). The sample consisted of 3,845 high school students in 2006. Physical inactivity was measured using the International Physical Activity Questionnaire (short IPAQ) and was defined as practicing moderate and/or vigorous physical activity for a period of less than 300 minutes per week. The independent variables analyzed were: gender, age, socioeconomic level, geographic area of the city, awareness of the "Agita São Paulo" program, participation in physical education classes, smoking, alcohol intake and time spent per day watching television. Three-level Poisson regression was used for assessing the variables, with a significance level of p < 0.05. RESULTS: The general prevalence of physical inactivity among adolescents in São Paulo was 62.5% (95%CI 60.5-64.1). The factors associated with physical inactivity were gender, age, socioeconomic level, geographic area of the city, awareness of the "Agita São Paulo" program, non-participation in physical education classes, smoking, alcohol intake and time spent per day watching television. CONCLUSION: It was concluded that the prevalence of physical inactivity among adolescents in São Paulo was high in all the geographic areas evaluated, and that sociodemographic and behavioral factors contributed significantly to physical inactivity.